(1) Field of the Invention
The present invention generally relates to methods and compositions useful for determining whether a patient has cancer or is at risk for cancer. More specifically, the invention relates to ELF3 gene compositions that are associated with cancer, particularly breast cancer, and methods using those compositions in cancer diagnosis.
(2) Description of the Related Art
References Cited
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U.S. Pat. No. 6,326,173.
U.S. Pat. No. 6,436,909.
The diagnosis of breast cancer requires great skill by pathologists to properly classify biopsies into current pathological groupings. The proper interpretation of pathological findings has great consequences to patients as it can determine the choice of treatment for primary cancer. However, there remains confusion about the relationship between different forms of breast cancer. For example, there is uncertainty as to how invasive lobular cancer is different from invasive duct carcinoma. It is also not known whether all forms of invasive duct carcinoma are the same.
In spite of burgeoning molecular genetic technology and widespread human genome sequence information, no unique genetic marker has been found for the most common forms of breast cancer. The BRCA I and II genes have been useful in identifying patients at risk for familial forms of breast and ovarian cancer, but only a small percentage of most breast cancers occur in patients with the BRCA abnormalities. BRCA genes can be tested from DNA isolated from peripheral blood but this technology is not offered routinely to most women with breast cancer. Gene chip technology allows scientists to look for overexpression or underexpression of otherwise normal genes. Studies with gene chips are beginning to reveal various patterns of gene expression in breast cancer cells that do not occur with normal cells. However, gene chip technology is complex and expensive and is currently performed on actual biopsy tissue, which is not always available.
Another genetic marker, the ELF3 gene, is overly expressed in intraductal carcinoma (also called ductal carcinoma in situ [DCIS]). The ELF3 protein belongs to the Ets family of transcription factors, which contain a helix-loop-helix motif that is required to bind in the major groove of DNA sequences centered over a conserved core GGAA/T motif, and which is important for HER2/neu function (Chang et al., 1997; Oettgen et al., 1997a; Tymms et al., 1997; Andreoli et al., 1997; Choi et al., 1998; Chang et al., 1999; Oettgen et al., 1999; Oettgen et al., 1997b).
The ELF3 gene, which has also been called ESE-1, ERT, jen, and ESX, is a member of the subfamily of ELF (E74-like-factor) genes. The human ELF3 gene contains 9 exons and 8 introns (Chang et al., 1999; Oettgen et al., 1999), is located on chromosome 1q32.1-32.2 (Oettgen et al., 1997a; Tymms et al., 1997), and its transcribed RNA product is ˜5.8 kb. It is thought to be expressed only in epithelial cells (Chang et al., 1997; Tymms et al., 1997; Brembeck et al., 2000) and its expression is induced during epidermal differentiation. The epithelial-specific expression pattern of ELF3 is unique among members of the Ets family, and to date very few epithelial-specific transcription factors have been identified. Its DNA-binding domain, conserved among all Ets family members, is located in exons 8 and 9 (Oettgen et al., 1999).
As a transcriptional regulatory gene, ELF3 overexpression or alteration may play a role in carcinogenesis. ELF3 mRNA is overexpressed in ductal carcinoma in situ (DCIS) (Id.) in which there is a high incidence of HER2-neu amplification and overexpression (Barnes et al., 1992). Excess chromosome 1 is common in breast cancer (as well as lung and prostate cancer), and ELF3 may be similarly amplified.
Currently, it is believed that DCIS is the precursor lesion of invasive duct carcinoma (Rosen, 2001a). DCIS apparently arises from the terminal duct-lobular unit where the cell of origin is believed to be a terminal ductal epithelial cell (Rosen, 2001a, Wellings, 1975). Many different forms of DCIS exist including comedo, cribiform, micropapillary and solid type (Rosen, 2001a). Diagnoses of these forms of DCIS have been increasing in part because mammography has played an increasingly major role in detecting these often non-palpable tumors. As many as 43% of tumors detected mammographically have been DCIS (Andersson, 1984; Sigfusson et al., 1983; Tabar et al., 1984; Verbeek et al., 1984; Fonseca et al., 1997). Invasive duct carcinoma is believed to occur when the ductal carcinoma cells breech the myoepithelial basement membrane and invade into the stroma. Invasive duct carcinoma is often found in conjunction with a DCIS lesion (Rosen, 2001a).
DCIS is generally distinctly different from lobular carcinoma which can also form both in situ-like lesions (lobular carcinoma in situ) and invasive lesions (invasive lobular carcinoma). Lobular carcinoma in situ arises from the lobular cell itself (Rosen, 2001b). Most authorities do not consider lobular carcinoma in situ as a neoplastic lesion but as an indicator of increased cellular activity. This increased cellular activity is associated with an increased risk of other forms of breast cancer notably DCIS and invasive duct carcinoma as well as invasive lobular carcinoma. Some authorities feel, however, that lobular carcinoma in situ is the precursor lesion of invasive lobular carcinoma. Lobular carcinoma in situ lesions are inconspicuous and non-palpable, are often multicentric, can form signet ring-like cells and are associated with a distinctive type of infiltration (Rosen, 2001a). Mucin can be seen in an intracytoplasmic location in these cells. C-adherins are absent from these lesions. The cellular origin of these lesions is presumed to be the lobular cell.
Currently there is no genetic marker present that distinguishes lesions of terminal duct origin from those of lobular origin. In biopsy material from neoplastic breast lesions, these different cancers can be distinguished using some stains of mucin, cytokeratin and C-adherin, but there is no useful genetic marker that distinguishes these different cancers.
There is thus a need for new genetic markers to identify breast cancer, particularly DCIS. The present invention provides such markers.